Polymeric Micellar Paclitaxel-Based Combination Therapy for Advanced Biliary Tract Cancer

Prior treatment

• Prior treatment with polymeric micellar paclitaxel or its analogues, or known hypersensitivity or intolerance to polymeric micellar paclitaxel, paclitaxel or its components, lenvatinib, or the planned immune checkpoint inhibitor.
• Patients with other active malignancies or other incompletely treated malignant tumors within the previous 5 years.
• Significant digestive tract diseases, including grade ≥3 digestive tract fistula or non-digestive tract fistula according to CTCAE version 5.0, history of gastrointestinal bleeding within the previous 6 months, clear gastrointestinal bleeding tendency, or grade ≥3 gastrointestinal bleeding events.
• Clinically significant cardiovascular and cerebrovascular diseases, including acute myocardial infarction, severe or unstable angina, cerebrovascular accident, transient ischemic attack within 6 months before enrollment, clinically significant heart failure, arrhythmia requiring treatment, uncontrolled hypertension despite antihypertensive therapy, or thromboembolic events within the previous 6 months.
• Untreated or active central nervous system metastases, leptomeningeal metastasis, or epilepsy requiring medical treatment. Patients with previously treated and stable brain metastases could participate if imaging showed no progression for at least 4 weeks before treatment initiation, neurological symptoms returned to baseline, and corticosteroids were not required for at least 7 days before treatment.

Other illness

• Active, known, or suspected autoimmune diseases requiring systemic treatment, or history of organ transplantation or allogeneic bone marrow transplantation. Patients with type 1 diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, or skin diseases not requiring systemic treatment were allowed if clinically appropriate.
• Persistent infection of CTCAE grade \>2, known active tuberculosis, or known HIV infection.

Lab values

• Severe hepatic or renal dysfunction, including jaundice, ascites, or bilirubin \>3×ULN; renal failure requiring dialysis; or clinically significant proteinuria. Patients who received strong CYP3A4 inhibitors within 7 days or strong CYP3A4 inducers within 12 days before study treatment were also excluded.

Other

• Histopathological results showing combined hepatocellular-cholangiocarcinoma, squamous cell carcinoma, sarcoma components, or ampullary carcinoma.

• The subjects voluntarily participated in the study, provided written informed consent, and were willing to comply with study treatment, assessments, and follow-up. Patients were ≥18 years old and \<75 years old at the time of signing informed consent, regardless of gender.
• Patients with advanced biliary tract carcinoma diagnosed by imaging and histology as unresectable, recurrent, locally advanced, or metastatic disease, defined as stage IIIA or above according to the AJCC 8th edition staging system, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. No more than two metastatic organ sites were allowed, including liver, lung, bone, and brain.
• Radical surgery or local treatment, including focal excision, ablation, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and radiotherapy, was not appropriate, or disease progression occurred after local treatment. At least 4 weeks should have elapsed after local treatment before baseline assessment, and acute toxicities related to prior treatment should have recovered to NCI-CTCAE version 5.0 grade 1 or lower.
• Patients had disease progression after, or intolerance to, first-line systemic therapy for at least 1 month and required subsequent palliative systemic treatment. Treatment-related adverse events should have recovered to NCI-CTCAE version 5.0 grade 1 or lower before enrollment.
• At least one measurable lesion according to RECIST version 1.1 (a measurable lesion with a longest diameter ≥10 mm by CT/MRI or an enlarged lymph node with a short-axis diameter ≥15 mm).
• ECOG performance status was 0-1 within 1 week before enrollment, and expected survival was ≥3 months as assessed by investigators.
• Active hepatitis B or hepatitis C patients were required to receive antiviral therapy. HBV DNA should be \<2,000 IU/mL (\<10⁴ copies/mL), and anti-HBV therapy should have been administered for at least 14 days before study entry and continued during treatment. HCV RNA-positive patients should receive antiviral therapy according to local standard treatment guidelines, with liver function abnormality no higher than CTCAE grade 1.
• Hematologic and organ function were adequate based on laboratory results obtained within 14 days prior to initiation of investigational therapy.
• Any clinically significant biliary obstruction should have been resolved before enrollment.
• Adequate renal function: serum creatinine ≤1.5×ULN or creatinine clearance \>50 mL/min.
• Women of childbearing potential agreed to abstain from sexual intercourse or use highly effective contraception with an annual failure rate of \<1% during treatment and for at least 6 months after the last dose.
• Male participants agreed to abstain from sexual intercourse or use appropriate contraception and agreed not to donate sperm.